Project Summary Bipolar disorder is a widespread and debilitating condition, yet its pathophysiology is poorly understood. Lithium is a widely used treatment, but its mechanism remains similarly uncertain. Evidence from animal studies, as well as human in vivo positron emission tomography (PET) studies, suggests that serotonin plays a large role in the disorder. In particular, the serotonin transporter (5-HTT) and the serotonin 1A (5-HT1A) receptor have been shown to function abnormally in bipolar subjects. In addition, an electroencephalography (EEG) paradigm known as the Loudness Dependence of the Auditory Evoked Potential (LDAEP), which is thought to relate inversely to serotonergic transmission, is altered in bipolar disorder. My study aims to examine the relationship between 5- HTT/5-HT1A activity and treatment response to lithium in bipolar disorder. I will examine this using both PET and EEG, to assess the neurochemical and electrophysiological profiles of serotonin function. A pilot study of five individuals with major depressive disorder showed a very strong correlation between LDAEP amplitude and 5- HT1A binding. Our results suggest that LDAEP may be a reliable indicator, not only of general serotonin function, but of specific binding potential. My study will test this hypothesis in the setting of bipolar disorder. First, the binding potential of 5-HTT and 5-HT1A receptors will be examined with PET and correlated with LDAEP amplitudes. A strong correlation will indicate a greater contribution of the receptor to the electrical signal. With this approach, I hope to improve the specificity of LDAEP analysis. Second, LDAEP will be examined in bipolar subjects before and after lithium treatment. Changes in LDAEP amplitude will provide evidence for changes in the serotonergic system. Initial amplitudes will also be correlated with treatment response to examine if LDAEP can serve as a response predictor. Finally, both PET and EEG will be used to assess differences between males and females in bipolar symptoms and treatments. As the disorder manifests itself differently between genders, I hope to improve understanding of this phenomenon. Greater biological understanding could help to advance pharmacological treatment. If positive results are found in this study, my findings may help explain the pathophysiology of bipolar disorder, while opening up EEG as a less expensive, more widely accessible, and noninvasive alternative to PET. In addition, by correlating EEG signal and 5-HT1A, I may be able to establish a cortical surrogate for subcortical receptor activity.